WO2002072091A1

WO2002072091A1 - Anticancer drug-tolerance inhibitors

Info

Publication number: WO2002072091A1
Application number: PCT/JP2002/002035
Authority: WO
Inventors: Hiroyoshi Hidaka; Toshihumi Mastuyama
Original assignee: D.Western Therapeutics Institute
Priority date: 2001-03-08
Filing date: 2002-03-04
Publication date: 2002-09-19
Also published as: JP2004359545A

Abstract

In clinical treatments of cancer, there arises a phenomenon that repeated use of an anticancer drug causes the acquisition of tolerance against the anticancer drug by cancer cells and thus the effect of the anticancer drug is weakened. Once cancer cells acquire tolerance against an anticancer drug, moreover, these cells become tolerant to a large number of other anticancer drugs (i.e., multidrug tolerance), which seriously interferes chemotherapy for cancer. Anticancer drug-tolerance inhibitors containing aminostilbazole derivatives represented by the formula (I) have low toxicity and can be orally administered. Thus, they can be safely used as anticancer drug-tolerance inhibitors. When these inhibitors are used together or formulated together into preparations with other anticancer drugs, tolerance of cancer cells against anticancer drugs can be inhibited and thus excellent anticancer effects can be established on tolerant cancer.

Description

Description Anticancer drug resistance inhibitor Technical field

The present invention relates to an anticancer drug resistance inhibitor for cancer cells, a method for suppressing cancer cell resistance to cancer cells, use of a specific compound for producing an anticancer drug resistance inhibitor, and a specific compound having an anticancer drug resistance inhibitory effect and another anticancer agent. , Or a combination drug. Background art

Until now, various anticancer chemotherapeutic agents have been used in the clinical treatment of cancer. However, it has been widely observed that when the same anticancer drug is used repeatedly, cancer cells become resistant to the anticancer drug, and the effect of the anticancer drug gradually decreases. Moreover, once a cancer cell has acquired resistance to one anticancer drug, it is often found that it also becomes resistant to many other antihealing agents with different chemical structures and mechanism of action. This is a phenomenon called multidrug resistance (MDR). The development of multidrug resistance of cancer cells to anticancer drugs has become a major obstacle to cancer drug therapy. ,

As one of the mechanisms by which cancer cells acquire resistance to anticancer drugs, the existence of a membrane protein having a pump function for pumping out anticancer drugs was confirmed on the cell membrane of cancer cells. The p-glycoprotein having a molecular weight of about 180,000 was identified as a protein having this pumping action (T suruo> T .: Jpn. J. Cancer. Res. 79: 285-296, 1988). ), And its entire cDNA structure was determined at the end of 1986 (Ger1ach, JHeta1: Nature 324: 485-489, 1985, Chem, C.—J., eta1: Ce1147). : 381—389, 1986). The pump function of this p-glycoprotein has low selectivity for anticancer drugs. Therefore, many anticancer drugs are also excreted from cancer cells, so that cancer cells expressing this protein are considered to have multidrug resistance. I have.

The MDR gene encoding p-glycoprotein forms the MDR 1 and MRD 2 gene families in humans, but is involved in anticancer drug resistance. Is only MDR1, and it has been shown that the expression of MDR1 in cancer cells correlates well with the acquisition of drug resistance in cancer cells in clinical practice.

If the expression of p-glycoprotein suppresses the acquisition of cancer cell resistance or cancels or attenuates the drug resistance acquired by the cancer cells, the response rate of anticancer drugs can be increased and cancer cell growth can be controlled over a long period of time. This would be a very useful tool. To date, calcium antagonists such as verapamil (Ts ur uo, T., eta 1: Cancer Re s. 41: 1967-1972, 1981, Ts ur uo, T., eta 1: Cancer res. 42: 4730—4733, 1982), calmodulin inhibitors, etc. (Gan ap athi. R, and G abos ws ki. D .: Cancer Re s. 43: 3696—3599,

1983), cyclosporin A (S later, LM, eta 1: J. CI inn. Invest. 77: 1405-1408, 1986), quinoline derivative (S at o. W., eta 1: C) ancer Re s. 51: 2420-

2424, 1991) have been reported to have an effect of suppressing drug resistance of cancer cells. However, these compounds do not suppress the expression of p-glycoprotein on the cancer cell membrane.For example, calcium antagonists have not yet been put to practical use because they have side effects such as lowering blood pressure, and they are effective and have side effects. It is desired to develop a very small number of anticancer drug resistance inhibitors. Disclosure of the invention

From the above viewpoints, the present inventors have searched for various compounds in search of compounds that suppress the resistance of cancer cells to anticancer drugs. As a result, the aminostilbazole derivative represented by the following formula [I] (hereinafter referred to as the present invention) Have been found to inhibit the expression of p-glycoprotein on cancer cell membranes and exert an inhibitory action on anticancer drug resistance, and have conducted further studies to complete the present invention.

That is, the present invention

(1) Equation (I)

[Wherein R ¹ and R ² are the same or different and are hydrogen, alkyl having 1 to 6 carbons, acyl having 1 to 6 carbons, cyano or —COOR (R is hydrogen or alkyl having 1 to 6 carbons) ).

R ³ , R ⁴ , R ¹³ and R ¹⁴ are the same or different and are hydrogen, alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, halogenoalkoxy having 1 to 6 carbons, 1 to carbons 6 acyl, 1-6 carbon acyloxy, hydroxy, halogen, nitro, cyano, amino, 1-6 carbon acylamino, 1-6 aminoalkoxy or morpholino alkyl containing 1-6 carbon Represents alkoxy. R ³ and R ¹³ or R ⁴ and R ¹⁴ may be independently taken together to represent methylenedioxy.

R ⁵ is, ① hydrogen, ② halogen, Amino, monoalkyl § amino having 1 to 6 carbon atoms, dialkylamino § amino having 1 to 6 carbon atoms, morpholino, Ku Wakashi alkoxy of 1 to 6 carbon atoms is substituted with hydroxy Represents an alkyl having 1 to 6 carbons which may be substituted, ③ an alkenyl having 2 to 6 carbons which may be substituted with halogen, アル an alkynyl having 2 to 6 carbons, or ⑤ an alkyl having 1 to 6 carbons.

R ⁶ is: (1) alkyl having 1 to 6 carbons, aroyl having 7 to 11 carbons which may be substituted with alkoxy or halogen having 1 to 6 carbons, or (2) alkyl having 1 to 6 carbons, C1 to C6 alkoxy, C1 to C6 halogenoalkoxy, C6 to C10 arylsulfonyl optionally substituted with hydroxy, nitro or halogen.

Y and Z each represent a ring.

-3 A, B, G, Q and X are the same or different and represent N or CH, or one of X and Q in Y ring or A, B or G in Z ring is N → 〇 or N +-(R ⁷ ) E— (R ⁷ is alkyl having 1 to 6 carbons or arylalkyl having 7 to 14 carbons; E— is a halogen ion, chlorate ion, nitrate ion, etc. Represents an ion). However, this does not apply when A, B, and G are simultaneously N and A, B, G, Q, and X are simultaneously CH. ]

An anticancer drug resistance inhibitor containing a compound represented by or a salt thereof,

(2) In the formula (I), RR ² is hydrogen, R ³ , R ⁴ , R ¹³ , and R ¹⁴ are the same or different and hydrogen, C 1-3 acyl, halogen or hydroxy, R ⁵ is hydrogen, Hydroxy-substituted alkyl having 1 to 3 carbon atoms or acyl having 2 to 4 carbon atoms, R ⁶ is phenylsulfonyl substituted with alkoxy having 1 to 3 carbon atoms, and ring Y is phenyl, Z The anticancer drug resistance inhibitor according to (1), wherein the ring is 4-pyridyl or its N-year-old oxide,

(3) In the formula (I), R ¹ and R ² are hydrogen, R ³ , R ⁴ , R ¹³ and R ¹⁴ are the same or different, and hydrogen, acetyl, fluorine or hydroxy, and R ⁵ is substituted with hydrogen or hydroxy. been Echiru or Asechiru, by R ⁶ are off We sulfonyl sulfonyl substituted with methoxy, and, Y ring is phenyl, Z ring is a 4 one pyridyl or N- old Kishido (1) anticancer drug resistance suppressed according Agent,

(4) The compound represented by the formula [I] is (E) -4- [2- [2- [N-[(p-methoxyphenyl) sulfonyl] amino] phenyl] ethenyl] pyridine and (E) -4 -[2-[2-[N-[:( p-methoxyphenyl) sulfonyl] amino] phenyl] ethenyl] 1-oxide, (E) -4- [2- [2- [2- [N- (2- N-[(p-methoxyphenyl) sulfonyl] amino] phenyl] ethenyl] pyridine 1-oxide, (E) —4— [2— [2— [N— (2-hydroxyethyl) 1) N-[:( p-methoxyphenyl) sulfonyl] amino] phenyl] ethenyl] pyridine, (E) —4— [2— [2— [N-acetyl-N-1 [(p-methoxyphenyl) sulfonyl] ] Amino] phenyl] ethenyl] pyridine 1-year-old oxide and (E) -4- [2-[2-[N-acetyl Rue N _ [(p-methoxyphenyl) sulfonyl] amino] phenyl] ethenyl] from pyridine The selected compound or a salt thereof, (1) the anticancer drug resistance inhibitor according to,

(5) an anticancer drug having suppressed anticancer drug resistance, which is obtained by combining the compound or a salt thereof shown in any of the above (1) to (4) with another anticancer drug;

(6) the anticancer agent according to (5), wherein the other anticancer agent is at least one selected from anthracycline, vin alkaloid and actinomycin anticancer agents;

(7) The other anticancer drug is at least one selected from adriamycin, evening sol, vincristine, vinblastine and cisbratin (5)

(8) an anticancer composition comprising the compound or salt thereof according to any one of (1) to (4) and another anticancer agent, wherein the anticancer agent resistance is suppressed.

(9) The anticancer composition according to (8), wherein the other anticancer agent is at least one selected from anthracycline-based, vin alkaloid-based, and actinomycin-based anticancer agents,

(10) the other anticancer agent is at least one selected from adriamycin, evening exol, vincristine, vinblastine and cisbratin; (8) the anticancer composition according to the above, wherein the anticancer drug resistance is suppressed;

(11) Use of the compound or a salt thereof described in any of the above (1) to (4) in producing an anticancer drug resistance inhibitor,

(12) a method for suppressing anticancer drug resistance of cancer cells, which comprises administering the compound or a salt thereof shown in any one of (1) to (4) to a cancer-affected mammal;

(13) A method for treating cancer, which comprises administering the compound or a salt thereof described in any of the above (1) to (4) and another anticancer agent to a mammal suffering from cancer,

(14) A method for treating cancer, comprising administering an anticancer composition comprising the compound shown in any of (1) to (4) or a salt thereof and another anticancer agent to a mammal suffering from cancer, and

(15) The method for treating cancer according to (12) to (14), wherein the mammal is a human.

The compound represented by the formula [I] is already known as an anticancer agent. However, the present invention is characterized in that the compound represented by the formula [I] has been found to have an anticancer drug resistance inhibitory effect on cancer cells having a different action mechanism from the anticancer effect. You. It has been completely known that the compound of the above formula [I] exerts an anticancer drug resistance inhibitory effect by suppressing the expression of p-glycoprotein, which is a cause of cancer cell resistance to anticancer drug, on the cancer cell membrane. Not.

Hereinafter, the present invention will be described in more detail.

“Inhibition of anticancer drug resistance” refers to suppressing the acquisition of cancer cell resistance to an anticancer drug or the acquisition of multidrug resistance (MDR) to multiple anticancer drugs having different structures and mechanisms of action. Means release or attenuation of the acquired anticancer drug resistance. In particular, it refers to the action of suppressing the expression of p-glycoprotein, which causes multidrug resistance, on the cancer cell membrane, thereby suppressing the acquisition of multidrug resistance of cancer cells.

Cancer is a concept of malignant neoplasm, including sarcoma, and cancer cells are of any type. As the “alkyl” in the formula [I], a linear or branched one having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl and the like. In particular, those having 1 to 3 carbon atoms are preferable.

“Alkoxy” includes linear or branched ones having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, Examples thereof include n-petyloxy, isopentyloxy, n-hexyloxy, isohexyloxy and the like. In particular, those having 1 to 3 carbon atoms are preferable.

“Alkenyl” includes straight-chain or branched ones having 2 to 6 carbon atoms, for example, ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 2-butenyl, 3-butenyl, Isobutenyl, methallyl, prenyl, isoprenyl, 1,1-dimethylaryl and the like can be mentioned. In particular, those having 2 to 4 carbon atoms are preferable.

“Alkynyl” includes straight-chain or branched ones having 2 to 6 carbon atoms, for example, ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 3-methyl-2-butynyl And the like. In particular, those having 2 to 4 carbon atoms are preferable.

"Acil" is a straight-chain or branched alkanol having 1 to 6 carbon atoms, for example, Examples thereof include formyl, acetyl, propionyl, butyryl, isoptyryl, valeryl, isovaleryl, pivaloyl, and the like, and may be substituted with halogen such as trifluoroacetyl. In particular, those having 2 to 4 carbon atoms are preferable.

Examples of the "aroyl" include those having 7 to 11 carbon atoms, such as benzoyl, hynapthoyl, / 3-naphthoyl and the like. Above all, benzoyl is preferred.

Examples of the "aryl" of arylsulfonyl include those having 6 to 10 carbon atoms, for example, phenyl, α-naphthyl, / 3-naphthyl and the like. In particular, phenyl is preferred.

Ariru such Aroiru or § reel sulfonyl are on the same or different one or more, may be substituted with substituents exemplified in the definition of R ^6.

"Halogen" includes chlorine, fluorine, bromine, and iodine. Examples of the "Υ" ring include phenyl, pyridyl, and pyrazinyl, and phenyl is preferable.Particularly, phenyl having a substituent-free force or phenyl having a substituent at a position adjacent to an amino group is preferred. preferable.

As the “Ζ” ring, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl and their p-oxides Among them, pyridyl is preferable, and among them, 4-pyridyl is preferable. Unsubstituted or 3-substituted 4-pyridyl and its dioxide are particularly preferable.

In the general formula [I], RR ² is hydrogen and one NR 5 R ⁶ is 4- (p-methoxyphenyl) sulfonylamino or N- (hydroxyethyl) -N-[(p-methoxyphenyl) sulfonyl] amino Wherein R ³ and R ¹³ are hydrogen or hydroxy, acetyloxy or fluorine and the Z ring is 4-pyridyl or its N-oxide, and R ⁴ and R ¹⁴ are hydrogen or hydroxy or methoxy and the Y ring is phenyl Compounds that are benzyl are preferred.

Examples of the salt of the compound [I] according to the present invention include salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, and hydrobromic acid, or acetic acid, tartaric acid, lactic acid, and citric acid. , Fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, Examples include salts of organic acids such as benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, and camphorsulfonic acid. Examples of the salt when Rl and R2 are carboxy include salts of alkali metals such as sodium, potassium, and calcium or alkaline earth metals.

The compound according to the present invention can be produced, for example, by the method described in International Publication WO95 / 27699.

Among the compounds according to the present invention,

(E) —4— [2 -— [2 -— [N-[(p-methoxyphenyl) sulfonyl] amino] phenyl] ethenyl] pyridine and its hydrochloride (compound 1),

(E) -4-1 [2 [2- [N-acetyl-N-[:( p-methoxyphenyl) sulfonyl] amino] phenyl] ethenyl] pyridine 1-year-old oxide (compound 2),

(E) —4— [2— [2_ [N— (p-methoxyphenyl) sulfonyl] amino] phenyl] ethenyl] pyridine 1-year-old oxide (compound 3),

(E) -4- [2- [2-[[N-acetyl-N-[; (p-methoxyphenyl) sulfonyl] amino] phenyl] ethenyl] pyridine (compound 4),

(E) -4- [2- [2-CN- (2-hydroxyethyl) -N-[(p-methoxyphenyl) sulfonyl] amino] phenyl] ethenyl] pyridine 1-oxoside (compound 5),

(E) —4— [2 -— [2 -— [N- (2-hydroxyethyl) _N — [(p-methoxyphenyl) sulfonyl] amino] phenyl] ethenyl] pyridine (compound 6) is preferable, and especially the compound 1 and 2 are preferred.

When the compound or a salt thereof is administered as an anticancer drug resistance inhibitor or a therapeutic agent for relapsed cancer or recurrent cancer, the compound may be used as it is or in a pharmaceutically acceptable nontoxic and inactive carrier, for example, It is administered to mammals including humans as a pharmaceutical composition containing 0.1 to 99.5% by weight, preferably 0.5 to 90% by weight.

As the carrier, one or more solid, semi-solid or liquid diluents, fillers and other auxiliaries for formulation are used. Desirably, the pharmaceutical compositions are administered in dosage unit form. The pharmaceutical composition of the present invention can be administered orally or parenterally (eg, injection, rectal). It is of course administered in dosage forms suitable for these administration methods It is. For example, oral administration is particularly preferred.

The dose as an anticancer drug resistance inhibitor or a therapeutic agent for relapsed or recurrent cancer is preferably prepared in consideration of the patient's condition such as age and weight, administration route, and the nature and extent of the disease. The amount of the active ingredient of the present invention for an adult is 0.1 mg to 50 Omg per day in the case of oral administration, preferably in the range of 1 mg to 20 Omg / human. is there. In some cases, lower doses may be sufficient and vice versa. It can also be administered in several divided doses per day.

Oral administration is performed in solid or liquid dosage units, such as powders, powders, tablets, dragees, capsules, granules, suspensions, solutions, syrups, drops, sublingual tablets, and other forms be able to.

Powders are prepared by comminuting the compound to an appropriate degree. Powders are prepared by comminuting the compound to a suitable fineness and then mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate such as starch, mannitol and the like. If necessary, flavoring agents, preservatives, dispersing agents, coloring agents, flavors and the like may be added. Force capsules are prepared by filling powdered powders, powders, or tablets as described above into granules as described in the section on capsules such as gelatin capsules. It is manufactured by Lubricants and superplasticizers, such as colloidal silica, talc, magnesium stearate, calcium stearate, and solid polyethylene glycol, are mixed with the powdered material, and then filled. Can also be performed. Adding disintegrants and solubilizers, such as carboxymethylcellulose, calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose, croscarmellose sodium, carboxymethyl sodium sodium, calcium carbonate, and sodium carbonate, makes the capsule It can improve the efficacy of the medicine when taken.

Further, the fine powder of the present compound can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, or a surfactant, and wrapped in a gelatin sheet to prepare a soft capsule.

Tablets are made by adding excipients to make a powder mixture, granulating or slugging, And disintegrating agents or lubricants are added to produce a tablet.

For the production of powder mixtures, the appropriate powdered material is mixed with the abovementioned diluents and bases, if necessary with binders (e.g. sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone). , Polyvinyl alcohol), a dissolution retardant (eg, paraffin), a resorbent (eg, quaternary salt) and an adsorbent (eg, bentonite, kaolin, dicalcium phosphate) can be used in combination. The powder mixture can be first moistened with a binder, for example, syrup, starch paste, gum arabic, cellulose solution or polymer solution, stirred and mixed, dried and ground to form granules. Instead of granulating the powder in this way, it is also possible to first apply the powder to a tableting machine and then crush the imperfect form of the obtained slag into granules. The granules thus produced can be prevented from adhering to each other by adding stearic acid, stearic acid salt, talc, mineral oil or the like as a lubricant. The mixture thus lubricated is then compressed. The uncoated tablets thus produced can be coated with a film coating sugar coating.

In addition, the present compound may be subjected to direct tableting after mixing with a fluid inert carrier without going through the steps of granulation and slag formation as described above. A transparent or translucent protective coating consisting of a shellac hermetic coating, a coating of sugar or a polymer material, and a polishing coating made of wax may be used. Other oral dosage forms, such as solutions, syrups and elixirs, can also be in dosage unit form so that a given quantity contains a fixed amount of the drug. Syrups are prepared by dissolving the compound in an appropriate flavored aqueous solution, and elixirs are prepared through the use of a non-toxic alcoholic carrier. Suspensions are formulated by dispersing the compound in a non-toxic carrier. Solubilizers and emulsifiers (eg, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters), preservatives, flavor enhancers (eg, ぺ mint oil, saccharin), etc., should also be added if necessary. Can be.

If necessary, dosage unit formulations for oral administration may be microencapsulated. The formulations may also be coated or embedded in polymers, waxes, etc. to increase the duration of action. A sustained release can also be provided. For parenteral administration, injections, suppositories and the like can be used. This can be done by using a liquid dosage unit for subcutaneous or intramuscular or intravenous injection, for example, a solution or suspension. For these, a certain amount of the compound is suspended or dissolved in a nontoxic liquid carrier suitable for the purpose of injection, such as an aqueous or oily catalyst, and the suspension or solution is sterilized. It is manufactured by Non-toxic salts or salt solutions may be added to make the injection solution isotonic. Furthermore, stabilizers, preservatives, emulsifiers, etc. can be used together.

For rectal administration, the compound can be treated with a low-melting, water-soluble or insoluble solid such as polyethylene glycol, cocoa butter, semi-synthetic fats and oils (such as Witebsol (registered trademark)), higher esters (such as (Myristyl palmitate) and suppositories produced by dissolving or suspending them in a mixture thereof.

The compound of the formula (I) or a salt thereof used in the present invention is administered to a cancer-affected mammal by combining it with another anticancer agent, particularly an anticancer chemotherapeutic agent, or as a combination containing them. The effect of the anticancer drug can be sufficiently exerted while suppressing the acquisition of the anticancer drug resistance of the cancer cells.

Further, the compound represented by the formula (I) or a salt thereof has low side effects and has an anticancer effect. Therefore, when combined with another anticancer agent or a combination of both, Single doses can also be reduced, in which case side effects from anticancer drugs can be significantly reduced.

Other anticancer agents to be combined with the compound of the formula [I] or a salt thereof include, for example, alkylating agents, topoisomerase inhibitors, antimetabolites, cytoskeletal inhibitors, enzymes, hormonal agents, hormone antagonists, antibiotics, plant-derived substances Examples thereof include tubulin agonists, and particularly preferred are anthracycline anticancer agents such as adoriamycin, macrolide anticancer agents such as taxol, and cisplatin.

When combining the compound represented by the formula (I) or a salt thereof with another anticancer agent, the two separately formulated agents may be administered simultaneously or at an appropriate interval to the mammal with cancer by the same administration route or different administration routes. Can be administered.

When a combination of the two is used, both components are desired according to the formulation technology described above. Can be prepared.

When the compound represented by the formula [I] or a salt thereof is used in combination with another anticancer agent, or when both components are used as a mixture, the ratio of the two components used is 1 to LZ when each is used alone. An appropriate amount can be selected from the range of 10. BRIEF DESCRIPTION OF THE FIGURES

Figure 1

P-Glycoprotein expression in SBC 3 / P and SBC 3 / ADR strains Figure 2

P-Glycoprotein expression level of SBC 3 ZAD R strain 6 hours after addition in medium with and without compound 1

Fig. 3

P-Glycoprotein expression level of SBC3 / ADR strain 12 hours after addition in medium with and without compound 1

Fig. 4

P-Glycoprotein expression level of SBC3ZADR strain 24 hours after addition in medium with and without compound 1

Fig 5

Cell growth inhibitory effect of adriamycin on SBC 3 / P and SBC 3ZADR strains

Fig. 6

Cell growth inhibitory effect of compound 1 on SBC 3ZP and SBC 3ZADR strains Figure 7

Cell proliferation inhibitory effect of mouse serum treated with compound 2 on SBC 3ZP and SBC 3 / ADR strains

Fig. 8

SBC 3 ZAD R strain Different amount of compound 2 Cell-suppressed mouse serum cell growth inhibitory effect

Explanation of reference numerals Thin solid line in Figure 1: SBC 3 ZP strain

Thick solid line: SBC 3ZADR strain

Dashed line in Fig. 2-4: SBC 3ZADR strain without compound 1

Solid line: Compound 1 added S B C 3 No AD R strain

Solid line in Figure 5: SBC 3ZP strain

Dashed line: SBC 3ADR strain

Solid line in Figure 6: SBC 3ZP strain

Dashed line: SBCZADR strain

Figure 7-1: Control serum-treated SBC3ZP strain

2: SBC3ZADR strain treated with control serum

3: SBC 3 / P strain treated with mouse serum of compound 2 administered 30 mgZkg of compound 2

4: Compound 2

Fig. 8-5: SBC3 ADR strain treated with control serum

6: SBC 3ZADR strain treated with mouse serum treated with 3 OmgZkg of compound 2

7: ^1001118/118 administration Mausu serum treatment of compound 2 38.3 // eight 01 ^ Co.

8: SBC 3 ZAD R strain treated with mouse serum administered with 30 OmgZkg of compound 2 Best mode for carrying out the invention

Example

Hereinafter, the present invention will be described specifically with reference to Examples, Comparative Examples, and Experimental Examples.

Example 1

(E) 1-4- [2-[2-[N _ [(p-methoxyphenyl) sulfonyl] amino] phenyl] ethenyl] pyridine (compound 1),

(E) 14- [2-[2-[N-acetyl-N _ [(p-methoxyphenyl) sulfonyl] amino] phenyl] ethenyl] pyridine 11-year-old oxide (compound 2),

(E) —4 -— [2-—2-CN-[(p-methoxyphenyl) sulfonyl] amino] phenyl] ethenyl] pyridine 1-oxide (compound 3) and (E) -4-1 [2- [2-[[N-acetyl-N-[(p-methoxyphenyl) sulfonyl] amino] phenyl] ethenyl] pyridine (compound 4)

As described below, the lung cancer cell line SBC 3ZP and its adriamycin-resistant strain SBC3 / ADR were cultured in Dulbecco's modified Eagle (DMEM) medium supplemented with 10% FCS, as described below. It was confirmed by analyzing with a flow cytometer or examining the cell growth inhibitory effect by the MTT method.

Experimental example 1

Each of the lung cancer cell line SBC3 / P and its adoriamycin-resistant strain SBC3ZADR were cultured in the above-mentioned medium for 2 days, and the expression of p-glycoprotein was compared by a pharmacocytometer. That is, the cultured cells were stained with an anti-human P-glycoprotein monoclonal antibody (Coulter, product number IM2370) and analyzed with a flow cytometer from Becton-Dickenson. SBC3ZADR expressed p-glycoprotein at a higher level than SBC 3 / P (Figure 1).

When compound 1 was added to the medium of the adriamycin-resistant cell line SBC3ZADR to a final concentration of 50 ng Zm1, compound 1 suppressed the expression of p-glycoprotein, and this effect increased over time. (Figure 2-4).

Experimental example 2

Spread 5 x 104 cells of the lung cancer cell line SBC3 / P and its adiamycin resistant strain SBC3 ZADR into a 96-well plate and add adriamycin or compound 1 to the culture medium.48 hours later, use the MTT assay to count the number of viable cells. Was counted, and the growth inhibitory activity of adriamycin or compound 1 was examined. SBC3NO ADR showed less inhibition of growth by adriamycin 5 Ong / ml than the parent strain SBC3ZP (FIG. 5).

Compound 1 also exhibited a marked growth inhibitory effect on the adoriamycin-resistant cell line SBC 3 ZADR as well as the J 巿 II cancer cell line SBC3 / P (FIG. 6).

In addition, Compound 3 was added to the medium at a final concentration of 50 ng / ml by the same method, and its growth inhibitory activity was examined. As a result, a cell growth inhibitory effect almost equivalent to Compound 1 was shown.

Experiment 3 38〇3? 5 and 104 of 8/3/801 in a 96-well plate, respectively, and 1 hour after administration of compound 2 (3 Omg / kg), mouse serum was serially diluted and added to the culture medium. As a control, the same amount of serum was added. 48 hours later, the number of viable cells was examined by MTT Atsey. The serum of the mouse to which Compound 2 was administered also showed a marked growth inhibitory effect on adriamycin-resistant cells SBC3ZADR as well as SBC3ZP (FIG. 7).

Spread 04 5 XIs of SBC 3 / ADR on each 96-well plate and add compound 2

Mouse sera to which 3 Omg / k, 10 Omg / kg, and 300 mgZkg were administered were serially diluted and added to the culture solution. As a control, the same amount of serum was added. After 72 hours, the number of viable cells was examined by MTT Atsey. Compound 2 showed an inhibitory effect on the growth of the adoriamycin-resistant cell line SBC3ZADR depending on the dose (FIG. 8).

In the same manner, mouse serum treated with 1.5 mg / kg, 5 mgZkg, and 15 mgZkg of compound 4 was serially diluted and added to the culture solution. ADR showed a growth inhibitory effect.

Example 2

Acute toxicity

Five week old CDF1 male mice were used. Compound 1 and compound 2 were each suspended in 0.5% methylcellulose, and orally administered once using an oral probe. The LD50 value was calculated from the number of deaths two weeks later by the Probit method. As a result, the LD50 of Compound 1 was 495 mgZkg, and the LD50 of Compound 2 was 705 mg / kg or more, indicating extremely low toxicity.

From the above results, it is clear that the compound according to the present invention has extremely low toxicity and high safety.

From the results of Experimental Examples 1 to 3 and Example 2 in Example 1 above, it was clarified that the compound according to the present invention had a very excellent anticancer drug resistance inhibitory action and low toxicity.

Prescription example 1

Hard force capsule (hard capsule) Compound 21 Omg

Lactose 187mg

Microcrystalline cellulose 2 Omg

Magnesium stearate 3mg

After weighing in the proportions of the above components and mixing uniformly, a No. 2 capsule was filled using a capsule filling machine to produce hard capsules. Prescription example 2

Granules 1 g of granules

Compound 11 Omg

Lactose 88 Omg

Low substituted hydroxypropylcellulose 7 Omg

Hydroxypropyl cellulose 4 Omg

After the above components were uniformly mixed and kneaded, the mixture was granulated to a diameter of 0.7 mm with a granulator to produce a granule. Prescription example 3

Hard capsule in 20 mg

Compound 21 Omg

Cisplatin lmg

Lactose 186mg

Microcrystalline cellulose 2 Omg

Magnesium stearate 3mg

After weighing in the proportions of the above components and mixing uniformly, 220 mg of No. 2 force capsules were filled using a capsule filling machine to produce hard capsules. Prescription example 4

Tablets (1 tablet 180 g)

Compound 3 5mg Cisplatin lmg Lactose l O Omg

Low-substituted hydroxypropylcellulose 9mg

Polyvinyl alcohol (40 mg corn starch 59 mg)

Lmg magnesium stearate

After uniformly mixing the components except polyvinyl alcohol and magnesium stearate, granules for tableting were produced by wet granulation using polyvinyl alcohol as a binder. This was mixed with magnesium stearate, and a tablet having a diameter of 8 mm and a size of 18 Omg was produced using a punching machine.

Industrial applicability

INDUSTRIAL APPLICABILITY The present invention has a strong anticancer drug resistance inhibitory action on cancer cells, has low toxicity, and can be orally administered, and thus can be used safely as an anticancer drug resistance inhibitor. In addition, when used in combination with or in combination with other anticancer agents, it is possible to suppress the resistance of cancer cells to the anticancer agent and to exert an excellent anticancer effect against resistant cancer. In addition, the sensitivity of cancer cells that have already been made resistant to the anticancer drug by administration of the anticancer drug resistance inhibitor of the present case can be regenerated.

That is, the present invention suppresses anticancer drug resistance in chemotherapy of various types of malignant tumors such as lung cancer, breast cancer, gastrointestinal cancer, prostate cancer, hematological cancer, and sarcoma, and confirms the effect on chemotherapeutic agents against cancer. Things.

Claims

The scope of the claims

Formula (I)

[Wherein 1 and ² are the same or different and are hydrogen, alkyl having 1 to 6 carbons,

6 represents acyl, cyano or —C〇〇R (R is hydrogen or alkyl having 1 to 6 carbons).

R ³ , RR ^13, and R ¹⁴ are the same or different and are hydrogen, alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, halogenoalkoxy having 1 to 6 carbons, 1 to 6 carbons 1 to 6 carbon atoms, oxy, hydroxy, halogen, nitro, cyano, amino, 1 to 6 carbon atoms, aminoalkoxy with 1 to 6 carbon atoms, or morpholinoalkoxy with 1 to 6 carbon atoms in the alkyl moiety. Represent. R ³ and ¹³ or R ⁴ and R ¹⁴ may be independently taken together to represent methylenedioxy.

R ⁶ is: (1) alkyl having 1 to 6 carbons, aroyl having 7 to 11 carbons which may be substituted by alkoxy or halogen having 1 to 6 carbons, or (2) alkyl having 1 to 6 carbons, Alkoxy having 1 to 6 carbon atoms, halogenoalkoxy having 1 to 6 carbon atoms, 6 to 10 carbon atoms which may be substituted with hydroxy, nitro or halogen Represents arylsulfonyl.

Y and Z each represent a ring.

A, B, G, Q and X are the same or different and represent N or CH, or one of X and Q in Y ring or A, B or G in Z ring is N → 0 or N + one (R ⁷ ) E— (R ⁷ represents alkyl having 1 to 6 carbon atoms or arylalkyl having 7 to 14 carbon atoms, and E_ represents an anion such as octagene ion, chlorate ion, nitrate ion, etc. ).

Excludes when A, B, and G are simultaneously N, and when A, B, G, Q, and X are simultaneously CH. ]

An anticancer drug resistance inhibitor comprising a compound represented by the formula: or a salt thereof.

2. In the formula [I], R ¹ and R ² are hydrogen, R ³ , R ⁴ , R ¹³ and R ¹⁴ are the same or different and hydrogen, C 2-4 acyl, halogen or hydroxy, and R ⁵ is hydrogen , alkyl of 1-3 carbons substituted with hydroxy shea, or, Ashiru C2-4, and ring Y is phenylene Le a phenylalanine alkylsulfonyl R ⁶ is substituted by alkoxy of 1-3 carbon atoms 2. The anticancer drug resistance inhibitor according to 1., wherein the Z ring is 4-pyridyl or its N-oxide.

3. In the formula [I], RR ² is hydrogen, R ³ , R ⁴ , R ¹³ , and R ¹⁴ are the same or different and hydrogen, acetyl, fluorine or hydroxy, R ⁵ is hydrogen or hydroxy-substituted ethyl, or Acetyl, phenylsulfonyl in which R ⁶ is substituted with methoxy, ring Y is phenyl, ring Z is 4-pyridyl or N-oxide thereof. 1. The anticancer drug resistance inhibitor according to the above.

4. When the compound represented by the formula [I] is (E) —4- [2- [2- [N-[(p-methoxyphenyl) sulfonyl] amino] phenyl] ethenyl] pyridine, (E) —4— [ 2- [2-CN-[(p-Methoxyphenyl) sulfonyl] amino] phenyl] ethenyl] 1-oxide, (E) —4— [2— [2-CN- (2-hydrexyl) —N — (: (P-methoxyphenyl) sulfonyl] amino] phenyl] ethenyl] pyridine 1-oxide, (E) -4- [2— [2— [N— (2-hydroxyethyl) —N— [(P-methoxyphenyl) sulfonyl] amino] phenyl] ethenyl] pyridine, (E) —4— [2— [2— [N-acetyl-N 1 (: (P-methoxyphenyl) sulfonyl] amino] phenyl] ethenyl] pyridine 1-oxide and (E) -4- [2- [2- [N-acetyl-NC (p-methoxyphenyl) 1. The anticancer drug resistance inhibitor according to 1., which is a compound selected from sulfonyl] amino] phenyl] ethenyl] pyridine or a salt thereof.

5. An anticancer drug having suppressed anticancer drug resistance, which is obtained by combining the compound or salt thereof shown in any one of the above 1 to 4 with another anticancer drug.

6. The anticancer agent according to the above 5, wherein the other anticancer agent is at least one selected from anthracycline-based, vin alkaloid-based, and actinomycin-based anticancer agents.

7. The anticancer agent according to 5., wherein the other anticancer agent is at least one selected from adriamycin, taxol, vincristine, vinblastine, and cisbratin.

8. An anticancer composition comprising the compound or salt thereof described in any one of the above 1 to 4 and another anticancer agent, wherein the anticancer agent resistance is suppressed.

9. The anticancer composition according to the above item 8, wherein the other anticancer agent is at least one selected from anthracycline, vin alkaloid, and actinomycin anticancer agents.

10. The anticancer composition as described in 8. above, wherein the other anticancer agent is at least one selected from adriamycin, taxol, vincristine, vinblastine and cisbratin.

11. Use of the compound or a salt thereof described in any one of the above 1 to 4 in the production of an anticancer drug resistance inhibitor.

12. A method for suppressing cancer cell resistance to an anticancer drug, which comprises administering the compound or a salt thereof described in any one of the above items 1 to 4 to a diseased mammal.

13. A method for treating cancer, which comprises administering the compound shown in any one of 1 to 4 or a salt thereof and another anticancer agent to a mammal suffering from cancer.

14. A method for treating cancer, comprising administering an anticancer composition comprising the compound shown in any one of the above 1 to 4 or a salt thereof and another anticancer agent to a mammal suffering from cancer.

15. The method for treating cancer according to 12. to 14., wherein the mammal is a human.